As a mechanism of self defense, animals have developed a complex series of responses to foreign materials, collectively called the immune system. Immune responses are generally advantageous (i.e., protective) by nature. However, in certain situations, the animal body produces an immune response that is undesirable. Normally, the immune system recognizes and reacts to a vast variety of molecules, or antigens. Appropriate immune responses include the inactivation and clearance of foreign agents (such as bacteria or viruses), and surveillance against internally arising anomalies such as tumors. Inappropriate or excessive activation of the immune system, however, can cause several classes of disease, notably autoimmune disease and allergy. Autoimmune disease occurs when the immune system recognizes integral body components as if they were foreign and attacks them accordingly. Allergies occur when essentially innocuous extrinsic antigens such as pollen, animal dander or drugs elicit characteristic Immunoglobulin E (IgE) antibodies. Disease symptoms may also be triggered by the presence of Immunoglobulin G (IgG) antibodies to extrinsic antigens (e.g., drugs). These symptoms arise when excessive amounts of these antigens are present in the body.
A small percentage of patients (approximately 3%) treated with sulfonamide drugs such as sulfamethoxazole (SMX) experience immunologically-mediated adverse reactions. These can range from mild symptoms such as urticaria or fever to life threatening reactions such as anaphylaxis.
In recent years, the number of patients reported to experience allergic reactions to sulfonamides has increased. This is believed to be largely due to the increasing numbers of acquired immuno-deficiency disease (AIDS) patients undergoing antibiotic treatment or prophylaxis for Pneumocystis carinii pneumonia (PCP). Before the advent of the AIDS epidemic, PCP was a rarely reported disease seen mostly in highly immunosuppressed individuals such as pediatric cancer patients or organ transplant patients. Between 1967 and the early 1990's the annual number of reported cases of PCP rose from 65 to more than 20,000, paralleling the advent of AIDS. Currently, PCP is the most commonly occurring opportunistic infection and cause of death in AIDS patients in the USA. The Center for Disease Control and Prevention has recommended that all human immuno-deficiency virus (HIV) positive individuals start continuous prophylaxis for PCP as soon as their CD4+ T cell count falls below 200 cells per microliter of blood. The most widely prescribed treatment is sulfamethoxazole-trimethoprim (SMX-TMP), but a substantial proportion (up to 60%) of patients experience adverse reactions to the SMX component. In a small minority (approximately 3%) of patients, these adverse reactions appear to be of the classical IgE-mediated type, but in the majority of cases the symptoms observed are more typical of an IgG-mediated syndrome. Individuals experiencing adverse reactions to SMX may be treated with other drugs, notably pentamidine or dapsone. However, the cost for these treatment regimens is higher, the efficacy lower, and patients may experience adverse reactions to the alternative drugs (Castellano et al. JAMA: (266), 820-24 (1991); Wood et al. N.E.J.Med.: (327), 1853-60 (1992)) . SMX has the added advantage in that it is effective against Toxoplasma gondii, another serious opportunistic infection in AIDS patients, whereas the alternative drugs have no effect on T. gondii.
As an alternative to changing drugs, patients may be desensitized to SMX with standard desensitization protocols similar to those used for penicillin-allergic individuals. Such desensitization has been carried out with some success in patients allergic to SMX (White et al. Ann. Allergy: (62), 177-79 (1992); Finegold et al. J. Allergy Clin. Immunol.: (78), 905-08 (1986)) . However, these desensitization regimens require great care and intensive monitoring to be safe and effective. In addition, any lapse in exposure to the drug in question (for example, through patient non-compliance) results in resensitization.
Individuals allergic to one drug have a higher than normal risk of developing sensitivity to other, often unrelated drugs. It would seem prudent, therefore, to treat the primary allergy itself, thus allowing utilization of the most effective course of therapy.
Patients at risk for developing allergic reactions to drugs (for example, those who have experienced previous reactions to the drug in question, or to other drugs), must be treated with great caution at the start of drug therapy. The ability to predict any given individual's antibody status (particularly with regard to IgE) and, hence, risk for adverse reactions, would be of great clinical utility. Although IgG antibody levels may be assessed accurately with standard ELISA techniques, these assays are time-consuming and cannot be used to determine IgE antibody levels accurately. The standard method for determining IgE status in patients is by intra-dermal or skin-prick testing. These tests are based on the ability of multivalent antigen to cross-link IgE molecules attached via a high affinity IgE receptor to the surface of mast cells present in the skin. Such receptor cross-linking triggers the mast cell to release vasoactive mediators such as histamine and serotonin, resulting in a classic wheal and flare reaction readily observable shortly after the injection. However, testing patients for SMX allergy by this means is not currently efficient or reliable as no suitable multivalent form of SMX is available. Injection of the monovalent drug may result in weak reaction, depending on the ability of metabolites of SMX to attach to proteins in the skin, thus forming multivalent arrays.
Thus, there exists a long-felt need for effective means of diagnosing, preventing and treating sensitization to SMX-containing compositions. Such a treatment should ideally remove the inappropriate B-cell response, rather than merely reducing the symptoms. The present invention satisfies this need and provides related advantages as well.